Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Clinical Associations and Prognostic Value of MRI-Visible Perivascular Spaces in Patients With Ischemic Stroke or TIA: A Pooled Analysis

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; p = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH.

Burden of cerebral small vessel disease and changes of diastolic blood pressure affect clinical outcome after acute ischemic stroke.

Elevated and low blood pressure (BP) may lead to poor functional outcome after ischemic stroke, which is conflicting. Hence, there must be another factor-such as cerebral small vessel disease (cSVD) -interacting with BP and thus, affecting outcome. Here, we investigate the relationship between BP and cSVD regarding outcome after stroke. Data of 423/503 stroke patients were prospectively analyzed. Diastolic (DBP) and systolic BP (SBP) were collected on hospital admission (BPad) and over the first 72 h (BP72h). cSVD-burden was determined on MR-scans. Good functional outcome was defined as a modified Rankin Scale score ≤ 2 at hospital discharge and 12 months thereafter. cSVD was a predictor of poor outcome (OR 2.8; p < 0.001). SBPad, DBPad and SBP72h were not significantly associated with outcome at any time. A significant relationship was found between DBP72h, (p < 0.01), cSVD (p = 0.013) and outcome at discharge. At 12 months, we found a relationship between outcome and DBP72h (p = 0.018) and a statistical tendency regarding cSVD (p = 0.08). Changes in DBP72h were significantly related with outcome. There was a U-shaped relationship between DBP72h and outcome at discharge. Our results suggest an individualized stroke care by either lowering or elevating DBP depending on cSVD-burden in order to influence functional outcome.

Dimethyl Fumarate Attenuates Lymphocyte Infiltration and Reduces Infarct Size in Experimental Stroke.

Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl fumarate (DMF) is known to modulate the immune response, activate antioxidative pathways, and improve the blood-brain barrier (BBB) after stroke. However, the specific impact of DMF on immune cells after cerebral ischemia remains unclear. In our study, male mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 min and received oral DMF (15 mg/kg) or a vehicle immediately after tMCAO, followed by twice-daily administrations for 7 days. Infarct volume was assessed on T2-weighted magnetic resonance images on days 1 and 7 after tMCAO. Brain-infiltrating immune cells (lymphocytes, monocytes) and microglia were quantified using fluorescence-activated cell sorting. DMF treatment significantly reduced infarct volumes and brain edema. On day 1 after tMCAO, DMF-treated mice showed reduced lymphocyte infiltration compared to controls, which was not observed on day 7. Monocyte and microglial cell counts did not differ between groups on either day. In the acute phase of stroke, DMF administration attenuated lymphocyte infiltration, probably due to its stabilizing effect on the BBB. This highlights the potential of DMF as a therapeutic candidate for mitigating immune cell-driven damage in stroke.

Deep Brain Stimulation in the Subthalamic Nucleus Can Improve Skilled Forelimb Movements and Retune Dynamics of Striatal Networks in a Rat Stroke Model.

Recovery of upper limb (UL) impairment after stroke is limited in stroke survivors. Since stroke can be considered as a network disorder, neuromodulation may be an approach to improve UL motor dysfunction. Here, we evaluated the effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) in rats on forelimb grasping using the single-pellet reaching (SPR) test after stroke and determined costimulated brain regions during STN-HFS using 2-[18F]Fluoro-2-deoxyglucose-([18F]FDG)-positron emission tomography (PET). After a 4-week training of SPR, photothrombotic stroke was induced in the sensorimotor cortex of the dominant hemisphere. Thereafter, an electrode was implanted in the STN ipsilateral to the infarction, followed by a continuous STN-HFS or sham stimulation for 7 days. On postinterventional day 2 and 7, an SPR test was performed during STN-HFS. Success rate of grasping was compared between these two time points. [18F]FDG-PET was conducted on day 2 and 3 after stroke, without and with STN-HFS, respectively. STN-HFS resulted in a significant improvement of SPR compared to sham stimulation. During STN-HFS, a significantly higher [18F]FDG-uptake was observed in the corticosubthalamic/pallidosubthalamic circuit, particularly ipsilateral to the stimulated side. Additionally, STN-HFS led to an increased glucose metabolism within the brainstem. These data demonstrate that STN-HFS supports rehabilitation of skilled forelimb movements, probably by retuning dysfunctional motor centers within the cerebral network.

A novel biomarker panel index improves risk stratification after ischemic stroke.

Background: We investigated 92 blood biomarkers implicated in the pathophysiological pathways of ischemic injury, inflammation, hemostasis, and regulation of vascular resistance to predict post-stroke mortality. Aim: Based on the most promising markers, we aimed to create a novel Biomarker Panel Index (BPI) for risk stratification. Methods: In this prospective study, we measured 92 biomarkers in 320 stroke patients. The primary outcome measure was mortality within 90 days. We estimated the association of each biomarker using logistic regression adjusting for multiple testing. The most significant 16 biomarkers were used to create the BPI. We fitted regression models to estimate the association and the discriminatory accuracy of the BPI with mortality and stroke etiology. Results: Adjusted for demographic and vascular covariates, the BPI remained independently associated with mortality (odds ratio (OR) 1.68, 95% confidence interval (CI): 1.29-2.18) and cardioembolic stroke etiology (OR 1.38, 95% CI: 1.10-1.74), and improved the discriminatory accuracy to predict mortality (area under the receiver operating characteristic curve (AUC) 0.93, 95% CI: 0.89-0.96) and cardioembolic stroke etiology (AUC 0.70, 95% CI: 0.64-0.77) as compared to the best clinical prediction models alone (AUC 0.89, 95% CI: 0.84-0.94 and AUC 0.66, 95% CI: 0.60-0.73, respectively). Conclusions: We identified a novel BPI improving risk stratification for mortality after ischemic stroke beyond established demographic and vascular risk factors. Furthermore, the BPI is associated with underlying cardioembolic stroke etiology. These results need external validation.

Changes of cerebral network activity after invasive stimulation of the mesencephalic locomotor region in a rat stroke model.

Motor deficits after stroke reflect both, focal lesion and network alterations in brain regions distant from infarction. This remote network dysfunction may be caused by aberrant signals from cortical motor regions travelling via mesencephalic locomotor region (MLR) to other locomotor circuits. A method for modulating disturbed network activity is deep brain stimulation. Recently, we have shown that high frequency stimulation (HFS) of the MLR in rats has restored gait impairment after photothrombotic stroke (PTS). However, it remains elusive which cerebral regions are involved by MLR-stimulation and contribute to the improvement of locomotion. Seventeen male Wistar rats underwent photothrombotic stroke of the right sensorimotor cortex and implantation of a microelectrode into the right MLR. 2-[18F]Fluoro-2-deoxyglucose ([18F]FDG)-positron emission tomography (PET) was conducted before stroke and thereafter, on day 2 and 3 after stroke, without and with MLR-HFS, respectively. [18F]FDG-PET imaging analyses yielded a reduced glucose metabolism in the right cortico-striatal thalamic loop after PTS compared to the state before intervention. When MLR-HFS was applied after PTS, animals exhibited a significantly higher uptake of [18F]FDG in the right but not in the left cortico-striatal thalamic loop. Furthermore, MLR-HFS resulted in an elevated glucose metabolism of right-sided association cortices related to the ipsilateral sensorimotor cortex. These data support the concept of diaschisis i.e., of dysfunctional brain areas distant to a focal lesion and suggests that MLR-HFS can reverse remote network effects following PTS in rats which otherwise may result in chronic motor symptoms.

Role of Blood-Based Biomarkers in Ischemic Stroke Prognosis: A Systematic Review.

BACKGROUND AND PURPOSE: Outcome prognostication in ischemic stroke patients remains challenging due to limited predictive properties of existing models. Blood-based biomarkers might provide additional information to established prognostic factors. We intended to identify the most promising prognostic biomarkers in ischemic stroke, their incremental prognostic value, and whether their predictive value differs among etiologies. METHODS: We searched MEDLINE (Ovid) and Institute for Scientific Information Web of Knowledge for articles reporting the predictive performance of blood-based biomarkers measured up to 7 days after ischemic stroke and reporting functional outcome or death at least 7 days after stroke. This work updates a previous systematic review (up to January 2007), follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and was registered (International Prospective Register of Systematic Reviews PROSPERO 2018; https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42018094671). RESULTS: Two hundred ninety-one articles published between January 2007 and August 2018 comprising 257 different biomarkers met inclusion criteria. Median sample size was 232 (interquartile range, 110-455); 260 (89%) articles reported regression analyses with 78% adjusting for stroke severity, 82% for age, 67% for both, and 9% for none of them; 37% investigated discrimination, 5% calibration, and 11% reclassification. Including publications from a previous systematic review (1960-January 2007), natriuretic peptides, copeptin, procalcitonin, mannose-binding lectin, adipocyte fatty acid-binding protein, and cortisol were the biomarkers most consistently associated with poor outcome in higher-quality studies showing an incremental value over established prognostic factors. Other biomarkers were less consistently associated with poor outcome or were reported in lower quality studies. High heterogeneity among studies precluded the performance of a meta-analysis. CONCLUSIONS: The number of reports on prognostic blood-based biomarkers in ischemic stroke increased 3.5-fold in the period January 2007 to August 2018. Although sample size increased, methodological flaws are still common. Natriuretic peptides and markers of inflammation, atherogenesis, and stress response are the most promising prognostic biomarkers among identified studies.

Mesencephalic Electrical Stimulation Reduces Neuroinflammation after Photothrombotic Stroke in Rats by Targeting the Cholinergic Anti-Inflammatory Pathway.

Inflammation is crucial in the pathophysiology of stroke and thus a promising therapeutic target. High-frequency stimulation (HFS) of the mesencephalic locomotor region (MLR) reduces perilesional inflammation after photothrombotic stroke (PTS). However, the underlying mechanism is not completely understood. Since distinct neural and immune cells respond to electrical stimulation by releasing acetylcholine, we hypothesize that HFS might trigger the cholinergic anti-inflammatory pathway via activation of the α7 nicotinic acetylcholine receptor (α7nAchR). To test this hypothesis, rats underwent PTS and implantation of a microelectrode into the MLR. Three hours after intervention, either HFS or sham-stimulation of the MLR was applied for 24 h. IFN-γ, TNF-α, and IL-1α were quantified by cytometric bead array. Choline acetyltransferase (ChAT)+ CD4+-cells and α7nAchR+-cells were quantified visually using immunohistochemistry. Phosphorylation of NFĸB, ERK1/2, Akt, and Stat3 was determined by Western blot analyses. IFN-γ, TNF-α, and IL-1α were decreased in the perilesional area of stimulated rats compared to controls. The number of ChAT+ CD4+-cells increased after MLR-HFS, whereas the amount of α7nAchR+-cells was similar in both groups. Phospho-ERK1/2 was reduced significantly in stimulated rats. The present study suggests that MLR-HFS may trigger anti-inflammatory processes within the perilesional area by modulating the cholinergic system, probably via activation of the α7nAchR.

Deep Brain Stimulation for Stroke: Continuous Stimulation of the Pedunculopontine Tegmental Nucleus has no Impact on Skilled Walking in Rats After Photothrombotic Stroke.

BACKGROUND: Gait impairment after stroke is considered as a loss of cerebral function but is also the result of dysfunctional cerebral signals travelling to the spinal motor centres. A therapeutic option to restore disturbed cerebral network activity is deep brain stimulation (DBS). METHODS: A promising target for neuromodulation might be the pedunculopontine tegmental nucleus (PPTg), which contributes to the initiation and control of gait. To test this hypothesis, we trained eighteen rats to cross a horizontal ladder and a wooden beam before inflicting a photothrombosis in the right sensorimotor cortex and implanting a stimulating electrode in the ipsilateral PPTg. RESULTS: Continuous high-frequency DBS (130 Hz; amplitude 55 ± 5 µA) of rats for 10 days yielded no significant improvement of skilled walking when examined with the ladder rung walking test and beam walking test compared to sham-stimulation. CONCLUSION: In contrast to DBS of the cuneiform nucleus, PPTg-stimulation improves neither control of gait nor balance after stroke.

SAA (Serum Amyloid A): A Novel Predictor of Stroke-Associated Infections.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate and independently validate SAA (serum amyloid A)-a recently discovered blood biomarker-to predict poststroke infections. METHODS: The derivation cohort (A) was composed of 283 acute ischemic stroke patients and the independent validation cohort (B), of 367 patients. The primary outcome measure was any stroke-associated infection, defined by the criteria of the US Centers for Disease Control and Prevention, occurring during hospitalization. To determine the association of SAA levels on admission with the development of infections, logistic regression models were calculated. The discriminatory ability of SAA was assessed, by calculating the area under the receiver operating characteristic curve. RESULTS: After adjusting for all predictors that were significantly associated with any infection in the univariate analysis, SAA remained an independent predictor in study A (adjusted odds ratio, 1.44 [95% CI, 1.16-1.79]; P=0.001) and in study B (adjusted odds ratio, 1.52 [1.05-2.22]; P=0.028). Adding SAA to the best regression model without the biomarker, the discriminatory accuracy improved from 0.76 (0.69-0.83) to 0.79 (0.72-0.86; P<0.001; likelihood ratio test) in study A. These results were externally validated in study B with an improvement in the area under the receiver operating characteristic curve, from 0.75 (0.70-0.81) to 0.76 (0.71-0.82; P<0.038). CONCLUSIONS: Among patients with ischemic stroke, blood SAA measured on admission is a novel independent predictor of infection after stroke. SAA improved the discrimination between patients who developed an infection compared with those who did not in both derivation and validation cohorts. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00390962.

Red flags for a concomitant giant cell arteritis in patients with vertebrobasilar stroke: a cross-sectional study and systematic review.

Giant cell arteritis (GCA) may affect the brain-supplying arteries, resulting in ischemic stroke, whereby the vertebrobasilar territory is most often involved. Since etiology is unknown in 25% of stroke patients and GCA is hardly considered as a cause, we examined in a pilot study, whether screening for GCA after vertebrobasilar stroke might unmask an otherwise missed disease. Consecutive patients with vertebrobasilar stroke were prospectively screened for GCA using erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin, and halo sign of the temporal and vertebral artery on ultrasound. Furthermore, we conducted a systematic literature review for relevant studies. Sixty-five patients were included, and two patients (3.1%) were diagnosed with GCA. Patients with GCA were older in age (median 85 versus 69 years, p = 0.02). ESR and CRP were significantly increased and hemoglobin was significantly lower in GCA patients compared to non-GCA patients (median, 75 versus 11 mm in 1 h, p = 0.001; 3.84 versus 0.25 mg/dl, p = 0.01, 10.4 versus 14.6 mg/dl, p = 0.003, respectively). Multiple stenoses/occlusions in the vertebrobasilar territory affected our two GCA patients (100%), but only five (7.9%) non-GCA patients (p = 0.01). Our literature review identified 13 articles with 136 stroke patients with concomitant GCA. Those were old in age. Headache, increased inflammatory markers, and anemia were frequently reported. Multiple stenoses/occlusions in the vertebrobasilar territory affected around 70% of stroke patients with GCA. Increased inflammatory markers, older age, anemia, and multiple stenoses/occlusions in the vertebrobasilar territory may be regarded as red flags for GCA among patients with vertebrobasilar stroke.

Two years' experience of implementing a comprehensive telemedical stroke network comprising in mainly rural region: the Transregional Network for Stroke Intervention with Telemedicine (TRANSIT-Stroke).

BACKGROUND: Telemedicine improves the quality of acute stroke care in rural regions with limited access to specialized stroke care. We report the first 2 years' experience of implementing a comprehensive telemedical stroke network comprising all levels of stroke care in a defined region. METHODS: The TRANSIT-Stroke network covers a mainly rural region in north-western Bavaria (Germany). All hospitals providing acute stroke care in this region participate in TRANSIT-Stroke, including four hospitals with a supra-regional certified stroke unit (SU) care (level III), three of those providing teleconsultation to two hospitals with a regional certified SU (level II) and five hospitals without specialized SU care (level I). For a two-year-period (01/2015 to 12/2016), data of eight of these hospitals were available; 13 evidence-based quality indicators (QIs) related to processes during hospitalisation were evaluated quarterly and compared according to predefined target values between level-I- and level-II/III-hospitals. RESULTS: Overall, 7881 patients were included (mean age 74.6 years ±12.8; 48.4% female). In level-II/III-hospitals adherence of all QIs to predefined targets was high ab initio. In level-I-hospitals, three patterns of QI-development were observed: a) high adherence ab initio (31%), mainly in secondary stroke prevention; b) improvement over time (44%), predominantly related to stroke specific diagnosis and in-hospital organization; c) no clear time trends (25%). Overall, 10 out of 13 QIs reached predefined target values of quality of care at the end of the observation period. CONCLUSION: The implementation of the comprehensive TRANSIT-Stroke network resulted in an improvement of quality of care in level-I-hospitals.

Relation of infarction location and volume to vertigo in vertebrobasilar stroke.

OBJECTIVE: Vertigo is a common presentation of vertebrobasilar stroke. Anecdotal reports have shown that vertigo occurs more often in multiple than in single brainstem or cerebellar infarctions. We examined the relation between the location and volume of infarction and vertigo in patients with vertebrobasilar stroke. METHODS: Consecutive patients with vertebrobasilar stroke were prospectively recruited. The infarction location and volume were assessed in the diffusion-weighted magnetic resonance imaging. RESULTS: Fifty-nine patients were included, 32 (54.2%) with vertigo and 27 (45.8%) without vertigo. The infarction volume did not correlate with National Institute of Health Stroke Scale (NIHSS) score on admission (Spearman ρ = .077, p = .56) but correlated with modified Rankin Scale (ρ = .37, p = .004) on discharge. In the vertigo group, the proportion of men was lower (53.1% vs. 77.8%, p = .049), fewer patients had focal neurological deficits (65.6% vs. 96.3%, p = .004), patients tended to present later (median [IQR] was 7.5 [4-46] vs. 4 [2-12] hours, p = .052), numerically fewer patients received intravenous thrombolysis (15.6% vs. 37%, p = .06), and the total infarction volume was larger (5.6 vs. 0.42 cm3 , p = .008) than in nonvertigo group. In multivariate logistic regression, infarction location either in the cerebellum or in the dorsal brainstem (odds ratio [OR] 16.97, 95% CI 3.1-92.95, p = .001) and a total infarction volume of >0.48 cm3 (OR 4.4, 95% CI 1.05-18.58, p = .043) were related to vertigo. In another multivariate logistic regression, after adjusting for age, sex, intravenous thrombolysis, serum level of white blood cells, and atrial fibrillation, vertigo independently predicted a total infarction volume of >0.48 cm3 (OR 5.75, 95% CI 1.43-23.08, p = .01). CONCLUSION: Infarction location in the cerebellum and/or dorsal brainstem is an independent predictor of vertigo. Furthermore, larger infarction volume in these structures is associated with vertigo. A considerable proportion of patients with vascular vertigo present without focal neurological deficits posing a diagnostic challenge. National Institute of Health Stroke Scale is not sensitive for vertebrobasilar stroke.

Proenkephalin A Adds No Incremental Prognostic Value After Acute Ischemic Stroke.

OBJECTIVE: The aim of this study was to confirm previous observations that proenkephalin A (PENK-A) may serve as prognostic marker in the setting of acute ischemic stroke in a large stroke cohort. METHODS: The plasma concentration of PENK-A was measured within 72 hours of symptom onset in 320 consecutively enrolled patients with stroke. The primary outcome measures were unfavorable functional outcome (modified Rankin Scale score 0-2 vs 3-6) and mortality within 90 days. Logistic and cox proportional regression analyses were fitted to estimate odds ratios (ORs), hazard ratios (HRs) and 95% confidence intervals (CIs), respectively, for the association between PENK-A and the primary outcome measures. RESULTS: After adjusting for demographic and vascular risk factors, PENK-A was neither independently associated with functional outcome (OR: 1.29, 95% CI: 0.16-10.35) nor mortality (HR: 1.02, 95% CI: 0.14-7.33). CONCLUSION: Among patients with acute stroke, PENK-A does not serve as an independent prognostic marker in this external validation cohort.

C-Terminal-Pro-Endothelin-1 Adds Incremental Prognostic Value for Risk Stratification After Ischemic Stroke.

Background and Aims: Endothelins have shown to play a role in the pathophysiology of ischemic stroke. We aimed at evaluating the incremental prognostic value of C-terminal-pro-endothelin-1 (CT-pro-ET-1) in a well-described cohort of acute stroke patients. Methods: We performed serial measurements of CT-pro-ET-1 in 361 consecutively enrolled ischemic stroke patients and assessed functional outcome and mortality after 90 days. As we found peak levels of CT-pro-ET-1 and the most prominent association with mortality on day 1 after admission (n = 312), we focused on this time point for further outcome analyses. We calculated logistic regression and cox proportional hazards models to estimate the association of CT-pro-ET-1 with our outcome measures after adjusting for demographic and clinical risk factors. To evaluate the incremental value of CT-pro-ET-1, we calculated the area under the receiver operating characteristics (AUC) curve and the continuous net reclassification index (cNRI) comparing the model with and without the biomarker CT-pro-ET-1. Results: In the univariate analysis CT-pro-ET-1 with a peak on day 1 after admission was associated with unfavorable outcome with an OR of 1.32 (95% CI, 1.16-1.51, p < 0.001) and with mortality with a HR of 1.45 (95% CI, 1.29-1.63, p < 0.001). After adjusting, CT-pro-ET-1 remained an independent predictor of mortality with an adjusted HR of 1.50 (95% CI, 1.29-1.74, p < 0.001), but not for functional outcome. Adding CT-pro-ET-1 to the cox-regression model for mortality, the discriminatory accuracy improved from 0.89 (95% CI, 0.84-0.94) to 0.92 (95% CI, 0.88-0.96) p < 0.001, and the cNRI was 0.72 (95% CI, 0.17-1.13). Conclusion: CT-pro-ET-1 with a peak level on day 1 was an independent predictor of mortality adding incremental prognostic value beyond traditional risk factors.

Corrigendum: Are Cerebral White Matter Lesions Related to the Presence of Bilateral Internal Carotid Artery Stenosis or to the Length of Stenosis Among Patients With Ischemic Cerebrovascular Events?

[This corrects the article DOI: 10.3389/fneur.2019.00919.].

Symptomatic vs. Asymptomatic 20-40% Internal Carotid Artery Stenosis: Does the Plaque Size Matter?

Background: Around 9-15% of ischemic strokes are related to internal carotid artery (ICA)-stenosis ≥50%. However, the extent to which ICA-stenosis <50% causes ischemic cerebrovascular events is uncertain. We examined the relation between plaque cross-sectional area and length and the risk of ischemic stroke or TIA among patients with ICA-stenosis of 20-40%. Methods: We retrospectively identified patients admitted to the Department of Neurology, University Hospital of Würzburg, from January 2011 until September 2016 with ischemic stroke or TIA and concomitant ICA-stenosis of 20-40%, either symptomatic or asymptomatic. Plaque length and cross-sectional area were assessed on ultrasound scans. Results: We identified 41 patients with ischemic stroke or TIA and ICA-stenosis of 20-40%; 14 symptomatic and 27 asymptomatic. The plaque cross-sectional area was significantly larger among symptomatic than asymptomatic ICA-stenosis; median values (IQR) were 0.45 (0.21-0.69) cm2 and 0.27 (0.21-0.38) cm2, p = 0.03, respectively. A plaque cross-sectional area ≥0.36 cm2 had a sensitivity of 71% and a specificity of 76% for symptomatic compared with asymptomatic ICA-stenosis. In a sex-adjusted multivariate logistic regression, a plaque cross-sectional area ≥0.36 cm2 and a plaque length ≥1.65 cm were associated with an OR (95% CI) of 5.54 (1.2-25.6), p = 0.028 and 1.78 (0.36-8.73), p = 0.48, respectively, for symptomatic ICA-stenosis. Conclusion: Large plaques might increase the risk of ischemic stroke or TIA among patients with low-grade ICA-stenosis of 20-40%. Sufficiently powered prospective longitudinal cohort studies are needed to definitively test the stroke risk stratification value of carotid plaque length and cross-sectional area in the setting of current optimal medical treatment.